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Miastenia Gravis Review
Miastenia Gravis Review
Clinical Medicine
Review
Myasthenia Gravis: Epidemiology, Pathophysiology and
Clinical Manifestations
Laura Dresser * , Richard Wlodarski, Kourosh Rezania and Betty Soliven
2. Epidemiology
MG is a rare neurological disease and pediatric MG is even more uncommon. Both
incidence and prevalence have significant geographical variations, but it is believed that
MG incidence has increased worldwide over the past seven decades. The prevalence
of MG was estimated at 1 in 200,000 from 1915 to 1934, increased to 1 per 20,000 after
the introduction of anticholinesterase drugs in 1934, and rose to 1 per 17,000 population
after the discovery of AChR antibodies in 1969 [12]. Prevalence rates range from 150 to
200 cases per million, and they have steadily increased over the past 50 years, at least partly
due to improvements in recognition, diagnosis, treatment, and an overall increase in life
expectancy [13]. More recent studies addressing incidence rates have been conducted in
Europe and show a wide range from 4.1 to 30 cases per million person-years [14,15].
The annual rate is lower in studies coming from North America and Japan, with the
incidence ranging from 3 to 9.1 cases per million [1]. Lower incidence and prevalence
rates have been reported in a large study from China at 0.155–0.366 per million, and
2.19–11.07 per 100,000, respectively [16]. Two population-based studies from Korea showed
a prevalence of 9.67–10.42 per 100,000 people in 2010, which increased to 12.99 per 100,000
in 2014 [17,18]. On the other hand, a smaller study using records of a hospital-based Health
Maintenance Organization estimated an incidence of MG at 38.8 per 1,000,000 person-years
for the Argentinian population [19]. Different study methodologies, including diagnostic
criteria and other sources of bias, such as the small size of the study population and the
underestimation of patients with milder disease, likely play a factor in the significant
variability of incidence rates over time and across different geographical regions.
Incidence rates have a bimodal distribution in women, with peaks around age 30 and
50. In men, the incidence increases steadily with age and with the highest rates between
age 60 and 89 [20]. Women are more commonly affected before age 40, with a female: male
ratio of 3:1 for early-onset MG. In the fifth decade of life, women and men are equally
affected, while men have a higher proportion after age 50, with a male: female ratio of
3:2 [21]. Around 10% of cases are pediatric, which is defined as onset before age 18 [13].
MG can affect people of all race and ethnic backgrounds and is slightly more prevalent in
patients of African ancestry [22–24]. Furthermore, MG phenotype may vary depending
on the ethnic background. In a retrospective study from South Africa, black patients were
more likely to have treatment-resistant ophthalmoplegia and ptosis than whites, whereas
the whites were more likely to develop treatment refractory generalized MG [25]. The age
at diagnosis was 17 years higher in Caucasians than non-Caucasians in another cohort
of patients with ocular MG [26]. In a US study, Oh et al. found that MG started earlier
and had a more severe phenotype in African Americans than in Caucasians [22]. The
seronegative African Americans had a higher percent of MuSK seropositivity in that study
(50% vs. 17% in the whites). On the other hand, patients of Asian ancestry have higher rates
of MuSK antibodies compared to Caucasians and individuals of African ancestry [27,28].
MuSK-associated MG is also more prevalent among those living in latitudes closer to the
equator [22,29].
The mortality rate of MG has dramatically declined from the early 20th century after
the availability of acetylcholine esterase inhibitors, immunosuppressants, intravenous
immunoglobulin and advanced respiratory care. However, the mortality rate from the
disease remains at 5–9%, being slightly higher in males than females [12]. Using the
US Nationwide Inpatient Sample (NIS) database for the years 2000 to 2005, the overall
in-hospital mortality rate was estimated as 2.2%, but higher in those with MG crisis
(4.7%), with the main predictors of death being older age and the presence of respiratory
failure [24].
J. Clin. Med. 2021, 10, 2235 3 of 17
Thymoma-Associated MG
MG is the most common paraneoplastic disorder associated with thymoma. Other
thymoma-related disorders with lower association rates include myositis, Morvan syn-
drome and pure red aplasia. About 50% of patients with a thymoma develop positive
AChR antibodies without clinical manifestations, and approximately 30% will develop
MG [57]. Conversely, 10–20% of patients with MG have thymomas [58]. Response to
thymectomy is variable, usually worse than in patients with EOMG [50]. Studies on HLA
alleles did not reveal a consistent association between HLA and thymomatous MG [59].
Lrp4, resulting in the reorientation of the Lrp4/MuSK complex, which in turn leads to
the activation of MuSK through its phosphorylation. Phosphorylated MuSK activates a
downstream signaling pathway that leads to the clustering of AChRs (Figure 1) [60].
Figure 1. Diagram depicting the secretion of agrin from the presynaptic membrane and its interaction
with Lrp4, which results in reorganization and reorientation of MuSK, promoting a signaling pathway
that leads to synaptic differentiation, including clustering of AChRs. This involves recruiting rapsyn
which links AChRs to the cytoskeleton (not shown).
Antibodies against MuSK are found in approximately 7–10% of all MG patients and
up to 40% of patients with generalized MG who are seronegative for AChR Abs. There is a
female predominance, with up to 85% of MuSK positive patients being female [61]. Animal
studies demonstrated that MuSK antibodies are pathogenic, as they cause severe weakness
when administered to healthy mice [62]. In contrast to AChR antibodies, MuSK antibody
titers correlate with disease severity [63]. The concurrence of seropositivity for both AChR
and MuSK antibodies has rarely been reported [64], but in general these are considered
distinct entities.
MuSK antibodies belong mainly to the IgG4 subclass. They do not fix complement and
are not strong activators of cell-mediated cytotoxicity [65]. Given the unique ability of IgG4
to undergo Fab arm exchange, MuSK antibodies are functionally monovalent, and they
cannot crosslink antigens of the same class. The mechanism by which MuSK antibodies
exert their pathogenic effect on the neuromuscular junction is via binding to the Ig-like
domain of the protein, preventing its phosphorylation, and subsequently disrupting the
Agrin-Lrp4-MuSK-Dok-7 signaling pathway. Dok-7 is a muscle-intrinsic activator of MuSK
and it is required for synaptogenesis [66]. This ultimately causes a reduction in the density
of AChRs in the postsynaptic membrane [67,68].
ptosis. Limb weakness can be uncommon, but when present it tends to be severe and
associated with muscle atrophy. Diurnal variations in strength are less common. There
is no clear association between MuSK-associated MG and thymic pathology [21]. From
the genetic predisposition standpoint, MuSK-associated MG has been associated with
DQB1*05 and HLA-DRB1*14/DRB1*16 [71,72].
Patients who are seropositive for both AChR and MuSK are rare, and it is not certain
if they should be categorized as an MG subtype. In a study from southern China, Zhang
et al. demonstrated that the phenotype of double-seropositive patients is more severe than
AChR-MG and more similar to the MuSK-associated MG [73].
4. Pediatric MG
Juvenile MG (JMG) is defined as MG in patients younger than 18 years of age. A
meta-analysis of epidemiological studies estimated the incidence of JMG between 1 and
5 cases per million person-years [1]. JMG is, however, more prevalent in the Asian than
the European populations. For example, Taiwanese and Japanese studies showed inci-
dence rates ranging from 3.7 to 8.9 per million person-years [1,79]. In other studies on
the Asian population, JMG constituted up to 50% of total MG cases, mostly of ocular
type [80,81]. There is also a higher prevalence in patients of African descent compared to
J. Clin. Med. 2021, 10, 2235 7 of 17
Caucasians [82,83]. Pediatric cases constituted 10–15% of total MG cases in a US study [13].
Similar to the young adults, JMG has a female preponderance [84,85].
A total of 16–38% of JMG cases are ocular [83,84]. Ocular JMG is more common in
pre-pubertal children, and post-pubertal children tend to have a greater proportion of
generalized MG [84–87]. As ocular symptoms often occur during critical times during
a child’s development, there is a risk for long-term sequelae such as strabismus and
amblyopia if this condition is not treated aggressively [88]. The generalization of symptoms
occurs in 20–25% of JMG patients [83,88], much lower than the rate of generalization in
adults, which can be up to 80% [12]. The course of generalized JMG is unpredictable and
may be associated with recurrent exacerbations including myasthenic crisis. On the other
hand, JMG patients may undergo periodic spontaneous remissions, at a higher rate than
the adults, often lasting for years [83,89].
Similar to adult-onset MG, the most common pathogenic antibodies detected in JMG
are AChR Ab, followed by MuSK and Lrp4. Fifty-three to 86% of generalized and ~40% of
ocular JMG patients are seropositive for AChR Abs [83,84,90]. It should be noted that ~40%
of patients seronegative for AChR Ab may become seropositive within 2 years of follow
up [89]. Up to 40% of JMG patients who are seronegative for AChR Ab are seropositive for
MuSK Abs [83,91]. Similar to adult-onset MG, anti-MuSK Ab seropositivity is predictive of
a more severe phenotype often associated with respiratory and bulbar muscle weakness
and atrophy. JMG may also be associated with anti-Lrp4 Ab, which manifests with a milder,
predominantly ocular phenotype [91,92]. In a large retrospective study from China, 13 of
455 (2.9%) patients who were seronegative for AChR and MuSK Abs had Lrp4 antibodies;
53.8% of them were children [92]. The pathogenesis of JMG is similar to the adult cases
and is described above.
JMG is a separate entity from transient neonatal MG, which occurs in 10–15% of
neonates born to mothers with MG as a result of the passive transfer of maternal antibodies
in utero [93,94]. While neonatal MG usually resolves spontaneously over weeks to months,
the affected infants may have generalized hypotonia, respiratory distress, poor suck in
addition to extraocular muscle weakness, necessitating the use of respiratory support,
treatment with neostigmine and, in severe cases, plasma exchange [93,94]. Furthermore,
the transfer of antibodies directed to fetal AChRs may result in persistent myopathic
features (i.e., fetal AChR inactivation syndrome), with symptoms ranging from mild facial
and bulbar weakness in the affected infants to arthrogryposis multiplex congenita [95].
Other JMG mimics include congenital myasthenic syndrome, mitochondrial diseases,
demyelinating polyneuropathies, and congenital myopathies. The asymmetric nature
of ptosis and ophthalmoparesis in ocular JMG may help distinguish it from congenital
myasthenic syndromes and mitochondrial diseases, as the extraocular weakness and
ptosis in the latter are usually, but not always, symmetrical [96]. Congenital myasthenic
syndromes are a particularly heterogeneous group of disorders and are beyond the scope
of this chapter.
5. Pathophysiology
5.1. Physiology and Organization of the Neuromuscular Junction
The neuromuscular junction is the site of impulse transmission between nerve ter-
minals and muscle fibers. This process requires the release of presynaptic acetylcholine
(ACh) and its subsequent binding to a postsynaptic ACh receptor. Synaptic vesicles con-
taining ACh are released from the presynaptic membrane after an action potential activates
voltage-gated calcium channels, allowing an influx of calcium into the nerve terminal [97].
The diffusion time of ACh through the synaptic cleft is very short, and it is modulated
by the enzyme ACh esterase (AChE), which promotes ACh degradation. The sponta-
neous release of synaptic vesicles generates the so-called miniature end plate potential
(MEPP), while upon nerve fiber stimulation/depolarization, a synchronous release of many
synaptic vesicles causes large depolarization of the end plate membrane, generating an
evoked endplate potential (EPP) (Figure 2). This, in turn, triggers an action potential in the
J. Clin. Med. 2021, 10, 2235 8 of 17
myofiber, which ultimately leads to its contraction. The amount of ACh released into the
synapse is usually higher than that required to generate an action potential, which allows
for reliable transmission [97,98]. The binding of ACh to its receptors in the postsynaptic
membrane opens the ACh cation-specific channel, leading to localized depolarization and
activation of adjacent voltage-gated sodium channels. This allows for the translation of the
chemical reaction into an electric signal, which is the muscle fiber action potential. The role
of AChE in the hydrolyzation of ACh is therefore crucial, as it prevents a single molecule
of ACh from repetitively activating AChRs. The effectiveness of neuromuscular junction
transmission is also determined by the amount of ACh released by the nerve terminal, the
density of ACh receptors in the postsynaptic membrane, and the density of voltage-gated
sodium channels at the endplate. The latter is dependent on the presence of folds in the
postsynaptic membrane. These folds determine the density of the voltage-gated sodium
channels in the postsynaptic membrane, and therefore increase the efficient coupling of the
localized EPP to the myofiber action potential [98].
Neuromuscular junction disorders such as MG disrupt the cascade of events that
lead to reliable muscle contraction. In addition, there is a reduction in the number of
AChRs and voltage-gated sodium channels as the result of complement-related injury to
the postsynaptic membrane in MG. The resultant inefficient neuromuscular transmission is
reflected in decremental response in the amplitude of compound muscle action potential
(CMAP) during repetitive nerve stimulation (RNS) and abnormal jitter or blocking in single
fiber EMG [98,99].
Figure 2. Neuromuscular transmission in normal individuals (A) and in patients with MG (B). Decreased density of the
AChR and complement-mediated damage to the postsynaptic membrane in MG patients result in decrease in miniature end
plate potential (MEPP), which occurs with spontaneous release of AChR vesicles, as well as endplate potential (EPP) in
response to nerve action potential of the presynaptic membrane. Diminished amplitude of EPP in MG results in impaired
neuromuscular transmission.
B cells and mature B cells that express polyreactive and autoreactive B cell receptors (BCRs)
is higher in both AChR-MG and MuSK-MG, which would support the concept that patients
with MG have defects in both central and peripheral B cell tolerance (Figure 3) [100]. As
a result, these patients are also at higher risk of developing other autoimmune diseases
such as systemic lupus erythematosus, rheumatoid arthritis, and thyroiditis. A break in
tolerance is also supported by data from deep sequencing of BCR repertoire showing
distinct gene segment usage biases in both VH and VL sequences within the naïve and
memory compartments in AChR-MG and MuSK-MG [101].
of anergy, or (3) clonal diversion/transformation into regulatory T cells (Tregs). The AChRs,
as well as other muscle proteins such as ryanodine and titin, are expressed by thymic myoid
and epithelial cells [103]. A key player in T cell autoimmunity is the autoimmune regulator
(AIRE) transcription factor, which induces tolerance over autoimmunity, by helping with
self-antigen expression in thymic cells. This transcription factor is modulated by estrogen,
which may help explain the early female predominance of the disease [104].
MG is uniquely associated with thymus hyperplasia and thymoma. The presence of
ectopic germinal centers is associated with early-onset AChR-MG, but not with MuSK-
associated MG. The T cell selection process may be impaired in thymic hyperplasia and
thymoma. The latter can have defective AIRE expression and can lack thymic medulla,
which is involved in the negative selection of T cells, therefore contributing to the release of
autoreactive CD4+ and CD8+ T cells [105]. In addition, the ensuing T cell subset imbalance
and cytokine dysregulation leads to the activation of B cells in germinal centers and
differentiation into autoreactive B cells and plasma cells [106]. T follicular helper cells
(Tfh), which are required for the generation of germinal centers, produce IL-21 and induce
immunoglobulin class switching [107]. Microarray analysis in thymic T cells from MG
patients revealed a Th1/Th17/Tfh signature [108].
Tfh in lymphoid organs are difficult to assess, so some investigators evaluate the
frequency of circulating Tfh (CXC5+ CD4 T cells in peripheral blood) instead. Ashida et al.
demonstrated an increase in circulating Tfh with elevated expression of inducible T cell
costimulator (ICOS) in a cohort of treatment naïve AChR-MG patients compared to con-
trols [109]. Interestingly, the frequency of circulating Tfh correlated with the severity of
MG, and its response to treatment in that study.
IL-17, IFN-γ, and GM-CSF and diminished IL-10 production [121]. On the other hand, T
cell and cytokine profile may change during MG crisis. Huan et al. demonstrated that
patients with MG crisis had significantly elevated levels of Th17 as well as Th2-related
cytokines IL-4 and IL-13 compared to 6 months post-ventilatory support [122]. Higher
frequencies of Th1 and Th17 cytokines were also observed in MuSK-associated MG [123].
During infections, there is likely a perturbation in the cytokine milieu that increases the
risk of MG exacerbation.
5.3.2. Regulatory T Cells (Tregs), Regulatory B Cells (Bregs), and B Cell-Activating Factor
(BAFF) Signaling in MG
Autoimmune diseases such as MG are precipitated when there is an altered balance
between autoreactive T and B cells, and regulatory cell types that suppress them. The
latter include Tregs and regulatory B cells, both of which are phenotypically diverse. Tregs
suppress the function of other effector T cells and antigen-presenting cells by releasing
anti-inflammatory cytokines, such as IL-10 and transforming growth factor beta (TGF-ß),
and through the expression of forkhead box protein 3 (FoxP3), among other mechanisms.
Th17/Treg imbalance has been reported in patients with MG, especially in those with
generalized forms and thymomatous MG [108,124]. Impaired suppressive function of
CD4+ Tregs from thymus and peripheral blood cells of MG patients has been demonstrated,
though the number of CD4+ Tregs was unchanged in most studies [125–128].
Regarding Bregs, multiple subsets of B cells with overlapping markers have been
reported to produce IL-10 and suppress pro-inflammatory responses, but the establish-
ment of consensus in the field has been hampered by the lack of a unique transcription
factor [129]. We and other investigators have reported that MG patients exhibited a de-
crease in the frequency of CD19+ CD1dhi CD5+ and CD19+ CD24hi CD38hi Breg subsets and
IL-10-producing B cells within each subset [130–133]. Taken together, the expansion of
Tregs and Bregs or the restoration of its suppressive function is a potential therapeutic
strategy in MG.
In contrast to the impaired number and/or function of Tregs and Bregs, there is some
evidence of enhanced BAFF signaling in MG. BAFF is a member of the tumor necrosis factor
family. BAFF signaling through interaction with BAFF-receptor (BAFF-R) is essential for B
cell survival, maturation, and their development into plasmablasts and plasma cells [134].
The levels of circulating BAFF, which is secreted by myeloid cells, are increased in the sera of
MG patients [135,136]. In addition, MG patients exhibit an increase in BAFF-R+ B cells [137].
These findings support a role for dysregulated BAFF signaling in MG pathogenesis.
6. Conclusions
MG affects all age groups, with peaks in younger women and older men. There is a
great variability in the geographical/regional rates of MG, with the incidence and preva-
lence rates increasing overall, the latter partly due to better awareness and improvements in
the diagnosis of the disease. Juvenile MG is more common in people of Asian and African
descent. A subset of AChR-MG is caused by a thymoma or thymic hyperplasia. The rest of
AChR-MG as well as all of MuSK, Lrp4, and seronegative-MG cases are primarily autoim-
mune in nature, though influenced by genetic background and environmental factors that
are fully understood. Although primarily an antibody-mediated disorder, different T and
B cell subsets, including Th2, Th1, Th17, Tfh, Treg and Breg, and their related cytokines
play important roles in MG pathogenesis. A deeper understanding of MG subgroups and
their distinct immunopathogenic mechanisms will result in the identification of therapeutic
targets and the development of targeted treatment strategies.
Author Contributions: L.D. drafted the manuscript. R.W. contributed to drafting the section on
pediatric MG. K.R. and B.S. revised the manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
J. Clin. Med. 2021, 10, 2235 12 of 17
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